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Process for the preparation of dexlansoprazole

a technology of dexlansoprazole and process, which is applied in the field of process for the preparation of dexlansoprazole, can solve the problems of removal of compound (b), complicated purification of this mixture, etc., and achieve the effects of high chemical purity, complete stereoselectivity, and a large mark

Inactive Publication Date: 2010-05-20
DIPHARMA FRANCIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]It has now been found a process for the preparation of Dexlansoprazole, or a salt thereof, which makes use of a sulphur intermediate of formula (III), as herein defined, which is cheap and largely available on the market. In particular the new process comprises the nucleophilic substitution of the nitro group in a compound of formula (II), as herein defined, and the stereoselective oxidation step of the starting compound of formula (III) as the last but one step of the synthesis. This makes the process of this invention more advantageous on industrial scale, when compared to the ones known in the art. In fact it allows preparing Dexlansoprazole on industrial scale, with a high chemical purity and substantially complete stereoselectivity and in an easy operating way.

Problems solved by technology

The purification of this mixture is often complicated and requires several crystallization steps to obtain a solid product sufficiently pure from a chemical and stereochemical point of view.
In particular removal of the compound (B) is a known problem in the production of chiral sulfoxides and is a real issue in the preparation of chiral sulfoxides on industrial scale.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of the (R)-2-[[[3-methyl-4-nitro-2-piridyl]-methyl]sulfinyl]benzimidazole (II)

[0037]A mixture of 2-[[3-methyl-4-nitro-2-piridyl]methylthio]benzimidazole (10 g, 33 mmoles, containing 70 mg of water) and (+)-diethyl-L-tartrate (3.02 g, 14.6 mmoles), in THF (100 ml) is brought to reflux temperature and maintained under stirring for 30 minutes. Titanium isopropoxide (1.89 g, 6.66 mmoles) is added and the mixture is maintained under stirring at reflux temperature till the formation of a clear solution is achieved. The solution is then cooled and added with diisopropylethylamine (1.42 g, 10.9 mmoles). After having achieved the range temperature between −5° C. and 0° C., the solution is treated by slow cooling with cumene hydroperoxide 88% (17.3 g, 100 mmoles). The reaction mixture is maintained under stirring for 3 hours at about 0° C., then treated with a 30% sodium thiosulphate solution to decompose the residue of cumene hydroperoxide. After the separation of the phases the aq...

example 2

Synthesis of Dexlansoprazole (I)

[0038]A solution of a compound of formula (II) (10 g, 31.5 mmoles), obtained by Example 1, in 2,2,2-trifluoroethyl alcohol (50 ml) is treated with Pd(PPh3)4 (36 mg, 0.031 mmoles) and potassium tert-butoxide (17.6 g, 157 mmoles). The so formed solution is maintained under stirring at a temperature of 80° C. for 4 hours and then cooled at room temperature. The reaction mixture is then quenched in water, extracted with methylethylketone. The phases are separated and the organic one is first diluted with water and then brought to pH 9 by adding sodium bisulfite. The phases are separated and the organic one is concentrated under reduced pressure. The residue is dissolved in acetone and then crystallized by adding water slowly to the solution. The obtained crystals are filtered, washed with acetone and copious water. After drying about 11 g of crystalline sesquihydrate Dexlansoprazole (yield 90%), with a purity higher than 99% and an enantiomeric excess hig...

example 3

Synthesis of Dexlansoprazole (I)

[0039]A solution of compound (II) (1.42 Kg) in 2,2,2-trifluoroethanol (6.40 L) is treated with potassium hydroxide (1.31 Kg). The reaction mixture is left to react at 90° C. for 1.5 hours and then cooled to 25° C. Water and toluene are added to the reaction mixture and the two newly formed phases are separated. Pure crystalline Dexlansoprazole sesquihydrate (1.56 Kg, 90% yield) can be isolated from the organic phase following the procedure reported in Example 2.

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Abstract

Process for the preparation of (R)-2-[[[3-methyl-4(2,2,2-trifluoroethoxy)-2-piridyl]methyl]sulfinyl]benzimidazole (Dexlansoprazole) and new intermediates useful in its preparation.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a process for the preparation of (R)-2-[[[3-methyl-4(2,2,2-trifluoroethoxy)-2-piridyl]methyl]sulfinyl]benzimidazole (Dexlansoprazole) and intermediates useful for its preparation.BACKGROUND OF THE ART[0002]Dexlansoprazole, namely (R)-2-[[[3-methyl-4(2,2,2-trifluoroethoxy)-2-piridyl]methyl]sulfinyl]benzimidazole, having formula (I), is the (R) enantiomer of Lansoprazole, which is a protonic pump inhibitor of the gastric parietal cells and therefore useful in therapy in the treatment of several disorders of the gastrointestinal tract.[0003]WO 96 / 02535 and EP 1277752 disclose the synthesis of Dexlansoprazole by stereoselective oxidation, according to the Kagan-Modena method, of the prochiral sulphur of formula (A) in toluene. Anyway, the stereoselective oxidation of the prochiral sulphur of formula (A), even if deeply studied, is a complex reaction when carried out on industrial scale and, generally, brings to the formation o...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor ATTOLINO, EMANUELELUCCHINI, VITTORIO
Owner DIPHARMA FRANCIS
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